Benzolactam Derivatives with D2 and D3 Receptor Affinity
(3-chloropropyl)piperazine (4a–f; 2.72 mmol) in 5 mL of benzene
was added dropwise. The mixture was held at reflux at 908C for
72 h, then the solvent was evaporated under reduced pressure.
The crude oil was purified by column chromatography (eluent:
EtOAc/hexanes, proportions depending on the compound); to
afford the title compounds 5–8 as dense oils, some of which cases
crystallized.
131.9, 130.5, 129.9, 128.5, 127.3, 127.2, 126.0, 119.0, 116.2, 112.5,
56.1, 53.4, 49.0, 46.8, 46.2, 28.6, 25.6; IR (film): 2943, 2824, 1646,
1488, 1451, 1314, 1238; MS (EI) m/z 417 ([M]+, 2), 243 (42), 217
(70), 186 (100), 160 (36), 118 (34); Chlorhydrate: light orange solid;
mp: 142–1458C; Anal. calcd for C23H26F3N3O·HCl·1.5H2O: C 57.44, H
6.29, N 8.74%, found: C 57.39, H 6.41, N 8.88%.
3,4-Dihydro-N-[3-(4-(2,3-dichlorophenyl)piperazin-1-yl)propyl]-
isoquinolin-1(2H)-one (5 f). Yellow solid, 86% yield; mp: 92–948C.
1H NMR (CDCl3): d=8.07 (dd, 1H, J=7.6, 1.1), 7.43–7.31 (m, 2H),
7.21–7.09 (m, 3H), 6.94 (dd, 1H, J=6.4, 3.3), 3.66–3.57 (m, 4H) 3.08
(brs, 4H), 2.99 (t, 2H, J=6.6), 2.68 (brs, 4H), 2.56–2.51 (m, 2H),
1.95–1.85 (q, 2H, J=7.3, 1.9); 13C NMR (CDCl3): d=164.8, 151.6,
138.3, 134.4, 131.9, 129.5, 128.6, 127.8, 127.4, 127.2, 126.2, 124.9,
119.0, 56.2, 53.7, 51.7, 46.7, 46.2, 28.6, 25.5; IR (KBr): 2941, 2821,
1646, 1575, 1451; MS (EI) m/z 417 ([M]+, 0.67), 382 (6), 243 (56),
217 (68), 186 (100), 160 (38), 118 (35); Chlorhydrate: white solid;
mp: 232–2368C (2-propanol); Anal. calcd for C22H25Cl2N3O·HCl: N
9.24, C 58.09, H 5.76%, found: N 9.31, C 58.01, H 6.07%.
3,4-Dihydro-N-[3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl]iso-
1
quinolin-1(2H)-one (5a). Viscous yellow liquid, 70% yield. H NMR
(CDCl3): d=8.07 (dd, 1H, J=7.6, 1.3), 7.43–7.31 (m, 2H), 7.17 (dd,
1H, J=7.8, 1.2), 7.02–6.84 (m, 4H), 3.85 (s, 3H), 3.66–3.56 (m, 4H),
3.10 (brs, 4H), 2.99 (t, 2H, J=6.6), 2.67 (brs, 4H), 2.53–2.48 (m,
2H), 1.89 (q, 2H, J=7.3); 13C NMR (CDCl3): d=164.8, 152.7, 142.0,
138.4, 131.9, 130.0, 128.6, 127.4, 127.2, 123.3, 121.4, 118.6, 111.6,
56.3, 55.7, 53.9, 51.0, 46.7, 46.2, 28.6, 25.6; IR (film): 2938, 1646,
1499, 1400, 1240; MS (EI) m/z 379 ([M]+, 8), 364 (29), 230 (32), 217
(79), 186 (100), 160 (43); Chlorhydrate: white solid; mp: 221–2228C;
Anal. calcd for C23H29N3O2·HCl·0.3CH3OH·0.7H2O: C 58.96, H 7.14, N
8.85%, found: C 58.95, H 7.15, N 8.88%.
2,3,4,5-Tetrahydro-N-[3-(4-(2-methoxyphenyl)piperazin-1-yl)pro-
pyl]benzo[c]azepin-1-one (6a). White solid, 26% yield; mp: 80–
3,4-Dihydro-N-[3-(4-(4-methoxyphenyl)piperazin-1-yl)propyl]iso-
quinolin-1(2H)-one (5b). White solid, 75% yield; mp: 76–778C (cy-
1
828C (cyclohexane). H NMR (CDCl3): d=7.66 (d, 1H, J=7.1), 7.38–
1
clohexane). H NMR (CDCl3): d=7.54 (dd, 1H, J=7.5, 1.2), 7.43–7.30
7.29 (m, 2H), 7.14–7.11 (m, 1H), 7.02–6.93 (m, 3H), 6.92–6.85 (m,
1H), 3.86 (s, 3H), 3.63 (t, 2H, J=7.4), 3.23 (t, 2H, J=6.4), 3.10 (brs,
4H), 2.79 (t, 2H, J=7.1), 2.69 (brs, 4H), 2.52 (t, 2H, J=7.5), 2.03 (q,
2H, J=6.8), 1.92 (q, 2H, J=7.5); 13C NMR (CDCl3): d=171.0, 153.0,
142.0, 138.0, 137.0, 131.1, 128.9, 128.5, 127.3, 123.30, 121.4, 118.6,
111.6, 56.4, 55.7, 53.9, 51.1, 46.9, 46.2, 30.7 30.4, 26.8; IR (KBr): 2941,
2819, 1708, 1632, 1499, 1454, 1372, 1239; MS (EI) m/z 378 ([M]+,
15) 231 (60), 202 (70), 134 (62), 120 (100), 91 (69); Chlorhydrate:
(m, 2H), 7.16 (d, 1H, J=7.4), 6.91–6.81 (m, 4H), 3.75 (s, 3H), 3.65–
3.56 (m, 2H), 3.09 (t, 4H, J=4.8), 2.99 (t, 2H, J=6.6), 2.67–2.65 (t,
4H, J=4.9), 2.51–2.46 (m, 2H), 1.88 (q, 2H, J=7.3); 13C NMR
(CDCl3): d=164.8, 154.2, 146.1, 138.4, 131.9, 130.01, 128.6, 127.4,
127.2, 118.5, 114.8, 56.2, 56.0, 53.8, 51.0, 46.8, 46.2, 28.6, 25.6; IR
(KBr): 2943, 2823, 1708, 1643, 1512, 1311; MS (EI) m/z 379 ([M]+,
97), 364 (78), 217 (100), 205 (43), 186 (69), 160 (43); Chlorhydrate:
white solid; mp: 216–2198C (dec.); Anal. calcd for
C23H29N3O2·2HCl·0.15CH3OH·0.75H2O: C 59.07, H 7.09, N 8.93%,
found: C 58.95, H 6.93, N 8.93%.
white
solid;
mp:
148–1498C;
Anal.
calcd
for
C24H31N3O2·2HCl·0.5H2O: N 8.84, H 7.21, C 60.63%, found: C 60.90,
H 7.48, N 8.77%.
3,4-Dihydro-N-[3-(4-(2-pyridyl)piperazin-1-yl)propyl]isoquinolin-
1(2H)-one (5c). White solid, 54% yield; mp: 91–928C (cyclohex-
ane). 1H NMR (CDCl3): d=8.19–8.17 (m, 1H), 8.08 (d, 1H, J=7.5),
7.49–7.31 (m, 3H), 7.17 (d, 1H, J=7.4), 6.65–6.59 (m, 2H), 3.66–3.48
(m, 8H), 2.99 (t, 2H, J=6.6), 2.57 (t, 4H, J=5.1), 2.50–2.45 (m, 2H),
1.89 (q, 2H, J=7.3); 13C NMR (CDCl3): d=164.5, 160.0, 148.3, 138.5,
137.8, 131.9, 130.0, 128.6, 127.4, 127.2, 113.7, 107.5, 56.3, 53.5, 46.8,
46.3, 45.6, 28.7, 25.6; IR (KBr): 2932, 1642, 1596, 1482, 1436, 1312,
1246; MS (EI) m/z 350 ([M]+, 8.5), 256 (44), 207 (84), 188 (91), 160
(46), 107 (100); Chlorhydrate: white solid; mp: 237–2388C; Anal.
calcd for C21H26N4O·2HCl·0.4CH3OH·0.6H2O: C 57.50, H 6.94, N
12.53%, found: C 57.50, H 6.94, N 12.53%.
2,3,4,5-Tetrahydro-N-[3-(4-(4-metoxyphenyl)piperazin-1-yl)pro-
pyl]benzo[c]azepin-1-one (6b). White solid, 41% yield; mp: 100–
1018C (cyclohexane). H NMR (CDCl3): d=7.66 (d, 1H, J=7.1), 7.36–
1
7.28 (m, 2H), 7.13 (d, 1H, J=7.05), 6.91 (d, 2H, J=8.90), 6.84 (d,
2H), 3.77 (s, 3H), 3.63 (t, 2H, J=7.3), 3.23 (t, 2H, J=6.3), 3.13–3.10
(m, 4H), 2.79 (t, 2H, J=7.0), 2.67–2.65 (m, 4H), 2.54–2.49 (m, 2H),
2.04 (q, 2H, J=6.7), 1.92 (q, 2H, J=7.4); 13C NMR (CDCl3): d=172.0,
154.1, 146.0, 138.0, 137.6, 131.1, 128.9, 128.6, 127.4, 118.6 (2C),
114.8 (2C), 56.3, 56.0, 53.8, 51.0, 46.9, 46.2, 30.7, 30.3, 26.7; IR (KBr):
2943, 1750, 1700, 1635, 1516; MS (EI) m/z 393 ([M]+, 15), 378 (19)
231 (87), 202 (100), 162 (43), 135 (51), 120 (50); Chlorhydrate: light
yellow
solid;
mp:
234–2368C;
Anal.
calcd
for
C24H31N3O2·HCl·0.1CH3OH·0.15H2O: C 66.4, H 7.56, N 9.64%, found:
C 66.37, H 7.61, N 9.64%.
3,4-Dihydro-N-[3-(4-(2-pyrimidyl)piperazin-1-yl)propyl]isoquino-
lin-1(2H)-one (5d). Yellow oil, 21% yield. H NMR (CDCl3): d=8.27
1
(d, 2H, J=4.7), 7.63 (dd, 1H, J=7.6, 1.3), 7.41–7.34 (m, 2H), 7.15 (d,
1H, J=7.4), 6.45 (t, 1H, J=4.7), 3.84–3.81 (m, 4H), 3.64–3.55 (m,
4H), 2.97 (t, 2H, J=6.6), 2.54–2.45 (m, 6H), 1.89 (q, 2H, J=7.3);
13C NMR (CDCl3): d=164.8, 162.0, 158.1, 138.3, 131.9, 129.9, 128.5,
127.4, 127.2, 110.2, 56.3, 53.5, 46.70, 46.2, 44.0, 28.6, 25.5; IR (film):
2940, 2852, 1646, 1600, 1550, 1500; MS (EI) m/z 351 ([M]+, 4), 243
(47), 186 (100), 148 (67), 122 (72); Chlorhydrate: light yellow solid;
mp: 216–2178C; Anal. calcd for C20H25N5O·2HCl·1.4H2O: C 53.43, H
6.68, N 15.58%, found: C 53.33, H 6.71, N 15.74%.
2,3,4,5-Tetrahydro-N-[3-(4-(2-pyridyl)piperazin-1-yl)propyl]ben-
zo[c]azepin-1-one (6c). White solid, 44% yield; mp: 104–1058C
(cyclohexane). 1H NMR (CDCl3): d=8.19 (dd, 1H, J=5.1, 1.6), 7.66
(dd, 1H, J=7.2, 1.7), 7.51–7.29 (m, 3H), 7.13 (d, 1H, J=5.8), 6.66–
6.60 (m, 2H), 3.64 (t, 2H, J=7.4), 3.58 (brs, 4H), 3.24 (t, 2H, J=6.4),
2.79 (t, 2H, J=7.1), 2.64 (brs, 4H), 2.52 (t, 2H, J=7.2), 2.09–2.02
(m, 2H), 2.02–1.91 (m, 2H); 13C NMR (CDCl3): d=171.5, 159.9, 148.3,
137.9, 137.6, 136.8, 131.1, 128.9, 128.6, 127.4, 113.8, 107.5, 56.4,
53.4, 46.9, 46.1, 45.3, 30.7, 30.3, 26.6; IR (KBr): 2942, 1750, 1635,
1615; MS (EI) m/z 364 ([M]+, 0.14), 258 (100), 243 (43), 227 (43),
165 (35); Chlorhydrate: off-white solid; mp: 233–2348C (EtOAc);
Anal. calcd for C22H28N4O·2HCl·H2O: N 12.3, C 58.02, H 7.08%,
found: N 12.29, C 58.14, H 7.24%.
3,4-Dihydro-N-[3-(4-(3-trifluoromethylphenyl)piperazin-1-yl)pro-
pyl]isoquinolin-1(2H)-one (5e). Yellow oil, 53% yield. 1H NMR
(CDCl3): d=8.08 (dd, 1H, J=7.6, 1.3), 7.43–7.31 (m, 3H), 7.17 (d,
1H, J=7.4), 7.10–7.03 (m, 3H), 3.66–3.57 (m, 4H), 3.24 (t, 4H, J=
5.03), 2.99 (t, 2H, J=6.6), 2.66–2.58 (m, 4H), 2.52–2.47 (m, 2H),
1.89 (q, 2H, J=7.3); 13C NMR (CDCl3): d=164.8, 151.8, 138.4, 132.0,
2,3,4,5-Tetrahydro-N-[3-(4-(2-pyrimidyl)piperazin-1-yl)propyl]-
benzo[c]azepin-1-one (6d). White solid, 27% yield; mp: 112–
ChemMedChem 2010, 5, 1300 – 1317
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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